title: Inhibition of phospholipase A2 in rat brain decreases the levels of total Tau protein.
abstract: The microtubule-associated protein Tau promotes the assembly and stability of microtubules in neuronal cells. Six Tau isoforms are expressed in adult human brain. All six isoforms become abnormally hyperphosphorylated and form neurofibrillary tangles in Alzheimer disease (AD) brains. In AD, reduced activity of phospholipase A(2) (PLA(2)), specifically of calcium-dependent cytosolic PLA(2) (cPLA(2)) and calcium-independent intracellular PLA(2) (iPLA(2)), was reported in the cerebral cortex and hippocampus, which positively correlated with the density of neurofibrillary tangles. We previously demonstrated that treatment of cultured neurons with a dual cPLA(2) and iPLA(2) inhibitor, methyl arachidonyl fluorophosphonate (MAFP), decreased total Tau levels and increased Tau phosphorylation at Ser(214) site. The aim of this study was to conduct a preliminary investigation into the effects of in vivo infusion of MAFP into rat brain on PLA(2) activity and total Tau levels in the postmortem frontal cortex and dorsal hippocampus. PLA(2) activity was measured by radioenzymatic assay and Tau levels were determined by Western blotting using the anti-Tau 6 isoforms antibody. MAFP significantly inhibited PLA(2) activity in the frontal cortex and hippocampus. The reactivity to the antibody revealed three Tau protein bands with apparent molecular weight of close to 40, 43 and 46 kDa in both brain areas. MAFP decreased the 46 kDa band intensity in the frontal cortex, and the 43 and 46 kDa band intensities in the hippocampus. The results indicate that in vivo PLA(2) inhibition in rat brain decreases the levels of total (nonphosphorylated plus phosphorylated) Tau protein and corroborate our previous in vitro findings.
authors.affiliation: Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, Rua Dr. Ovídio Pires de Campos, 785, São Paulo, SP, CEP 05403-010, Brazil. schaffer@usp.br
authors.forename: Evelin L
authors.initials: EL
authors.lastname: Schaeffer
authors.forename: Vanessa J
authors.initials: VJ
authors.lastname: De-Paula
authors.forename: Emanuelle R
authors.initials: ER
authors.lastname: da Silva
authors.forename: Barbara
authors.initials: B
authors.lastname: de A Novaes
authors.forename: Heni D
authors.initials: HD
authors.lastname: Skaf
authors.forename: Orestes V
authors.initials: OV
authors.lastname: Forlenza
authors.forename: Wagner F
authors.initials: WF
authors.lastname: Gattaz
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000008:administration & dosage; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005625:Frontal Lobe / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D063065:Organophosphonates / Q000008:administration & dosage; D064801:Phospholipase A2 Inhibitors; D054467:Phospholipases A2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; C489131:Mapt protein, rat; D063065:Organophosphonates; D064801:Phospholipase A2 Inhibitors; C104810:methyl arachidonylfluorophosphonate; D016875:tau Proteins; D054467:Phospholipases A2